Selectively brominated alkyl aryl and alkyl heteroaryl ketones are useful as intermediates in the preparation of various pharmaceuticals. Uses include, but are not limited to, intermediates in the preparation of norepinephrine potentiators (see, e.g., Kihara et al., Chem. Pharm. Bull. (1994), 42: 67--use of alpha-bromoacetophenone to prepare 4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols), anti-tumor antibiotics (e.g., Ogawa et al., Chem. Pharm. Bull. (1992), 40: 1315--use of alpha-bromopropiophenone to prepare guanine 7-oxides), antimicrobials (e.g., Rival et al., Chem. Pharm. Bull. (1992), 40: 1170--use of alpha-bromo ketones; e.g., alpha-bromo-4-chloroacetophenone, to prepare imidazopyrimidine derivatives), antifungals (e.g., Konosu et al., Chem. Pharm. Bull. (1990), 38: 2476--use of alpha-bromo-2,4,-dihalopropiophenones to prepare triazole antifungals), cyclooxygenase and 5-lipogenase dual inhibitors (e.g., Laufer et al., J. Med. Chem. (1994), 37: 1894--use of phenacyl bromides to prepare pyrrolizine derivatives), and 5-HT.sub.3 receptor antagonists (e.g., Rosen et al., J. Med. Chem. (1990), 33: 3020--use of alpha-bromo-2-methoxyacetophenone to prepare imidazolylthiazole derivative).
The base-catalyzed selective alpha-bromination of alkyl aryl ketones and alkyl heteroaryl ketones is generally difficult to achieve, because the presence of an alpha-bromine atom typically enhances the rate of further bromination at the alpha position. A substantially monobrominated product can be achieved by limiting the extent of reaction (e.g., by limiting the amount of brominating agent), but this results in a product mixture containing a substantial portion of unreacted starting ketone. On the other hand, if the bromination reaction is pushed to completion by the addition of more brominating agent, an overbrominated product results in which much of the product is di- and tri-brominated in the alpha-position.
One approach to obtaining only a monobrominated or only a dibrominated ketone product has been the selective monodebromination of overbrominated product. One method for selective monodebromination (see Bull et al., Tetrahedron Letters (1973), (44): 4349 and Posner et al., J. Amer Chem. Soc. (1973), 95: 3076) employs lithium dimethylcuprate, but this reagent is air, moisture and temperature sensitive, so that the reaction must be carried out under an inert atmosphere and at low temperature. Another method (see Lehman et al., Tetrahedron Letters (1976), 987 and Bakos et al., Steroids (1993), 58, 115) employs trimethylphosphite, but this reagent is environmentally unfriendly.